8a- and 9a-15-membered lactams

ABSTRACT

The invention relates to novel 15-membered 8a- and 9a-lactams from the class of 6-O-methyl-erythromycin A of general formula (I)                    
     their pharmaceutically acceptable addition salts with inorganic or organic acids and their hydrates, to intermediates for their preparation, to a process for their preparation, to their pharmaceutically acceptable addition salts with inorganic or organic acids, to their hydrates, to a process for the preparation of pharmaceutical compositions as well as to a use of pharmaceutical compositions for the treatment of bacterial infections.

TECHNICAL FIELD OF THE INVENTION

A61K 31/70, C07H 17/08

TECHNICAL PROBLEM

The invention relates to novel 15-membered 8a- and 9a-lactams from theclass of the macrolide antibiotic 6-O-methyl-erythromycin A, tointermediates for their preparation, to a process for their preparation,to their pharmaceutically acceptable addition salts with inorganic andorganic acids, to their hydrates, to a process for the preparation ofpharmaceutical compositions as well as to the use of pharmaceuticalcompositions for treatment of bacterial infections.

PRIOR ART

Erythromycin A is a macrolide antibiotic, whose structure ischaracterized by a 14-membered lactone ring with C-9 ketone and twosugars, L-cladinose and D-desosamine, glycosidically bound in C-3 andC-5 positions onto an aglycone moiety of the molecule (McGuire,Antibiot. Chemother. 1952; 2:281). By an oximation of C-9 ketone withhydroxylamine hydrochloride, by Beckmann rearrangement of the obtained9(E)-oxime and by a reduction of the formed 6,9-imino ether there isobtained 9-deoxo-9a-aza-9a-homoerythromycin A, the first semisyntheticmacrolide with a 15-membered azalactone ring (Kobrehel G. et al., U.S.Pat. No. 4,328,334, 5/1982). By means of a reductive methylation of9a-amino group, azithromycin, a prototype of a novel class of 9a-azalideantibiotics was synthesized (Kobrehel G. et al., BE 892 357, 7/1982). Inaddition to having a broad antimicrobial spectrum including alsoGram-negative bacteria, azithromycin is also characterized by a longbiological half-life, a specific transport mechanism to the site of useand a short therapy time. Azithromycin easily penetrates and accumulatesinside human fagocyte cells resulting in improved activity onintracellular pathogenic microorganisms, from classes Legionella,Chlamydia and Helicobacter.

It is known as well that by a O-methylation of C-6 hydroxyl groupclarithromycin (6-O-methyl-erhytromycin A) is obtained (Morimoto S. etal., J. Antibiotics 1984. 37. 187). In relation to erythromycin A,clarithromycin is much more stable in acidic medium and exhibitsimproved in vitro activity against Gram-positive bacterial strains(Kirst H. A. et al., Antimicrobial Agents and Chemother., 1989, 1419).

By recent research on 14-membered macrolides, a novel type of macrolideantibiotics. ketolides, has been discovered, whose structure ischaracterized by a 3-keto croup instead of a neutral sugar, L-cladinose(Agouridas C. et al., EP 596802 A1 5/1994; Le Martret O., FR 2697524 A15/94). Ketolides exhibit significantly improved in vitro activityagainst MLS (macrolide, lincosamide and streptogramin B)induced-resistant organisms (Jamjian C., Antimicrob. Agents Chemother.,1997, 41, 485).

It has been described as well that by Beckmann rearrangement of6-O-methyl-erythromycin A 9(E)- and 9(Z)-oximes, hydrolysis of cladinoseof the obtained 8a- and 9a-lactams, protection of 2′-hydroxyl group ofdesosamine, an acylation reaction, an oxidation of 3-hydroxyl group andby deprotection, there are obtained 15-membered 8a- and 9a-ketolidesfrom the class of 6-O-methyl-erythromycin A (Lazarevski G. et al.,PCT/HR 99/00004, 4/99).

According to known and established prior art, novel 15-membered 8a- and9a-lactams from the class of 6-O-methyl-erythromycin A, which are theobject of the present invention, their pharmaceutically acceptableaddition salts with organic or inorganic acids, their hydrates, methodsand intermediates for their preparation and methods for theirpreparation and use as pharmaceutical preparations have hitherto notbeen described. The object of this invention is preparation of11,12-substituted derivatives of 6-O-methyl-erythromycin A 8a- and9a-lactams and their 3-hydroxy and 3-keto derivatives. A further objectof the present invention are 3-acyl derivatives of6-O-methyl-erythromycin A 8a- and 9a-lactams and 3-acyl-derivatives of11,12-substituted 6-O-methyl-erythromycin A 8a- and 9a-lactams. Novel15-membered 8a- and 9a-lactams of the present invention are potentialantibiotics for the treatment of Gram-positive and Gram-negativesusceptible resistant strains.

DESCRIPTION OF TECHNICAL PROBLEMS WITH EXAMPLES

Novel 15-membered 8a- and 9a-lactams from the class of6-O-methyl-erythromycin A of the general formula (I)

their pharmaceutically acceptable addition salts with inorganic ororganic acids and their hydrates, wherein

A stands for NH group and B simultaneously stands for C═O group, or

A stands for C═O group and B simultaneously stands for NH group,

R¹ stands for OH group, L-cladinosyl group of formula (II)

or R¹ stands for a group of formula (III),

 wherein

Y stands for hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl group with at least oneincorporated O, N or S atom or Y stands for (CH₂)_(n)—Ar, wherein(CH₂)_(n) stands for alkyl and n stands for 1-10, with or withoutincorporated O, N or S atoms, and Ar stands for 5-10-membered monocyclicor bicyclic aromatic ring containing 0-3 O, N or S atoms, which isunsubstituted or substituted with 1-3 groups representing halogen, OH,OMe, NO₂, NH₂, amino-C₁-C₃ alkyl, amino-C₁-C₃ dialkyl, CN, SO₂NH₂, C₁-C₃alkyl, or

R¹ together with R² stands for ketone,

R² stands for hydrogen or together with R¹ stands for ketone,

R³ stands for hydrogen or C₁-C₄ alkanoyl group,

R⁴ stands for hydrogen or together with R⁵ stands for ketone,

R⁵ stands for OH, NH₂, amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl,O(CH₂)_(n)Ar or S(CH₂)_(n)Ar, wherein (CH₂)_(n) and Ar have the abovemeanings, or together with R⁴ stands for ketone,

R⁶ stands for hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl group with at least oneincorporated O, N or S atom, or (CH₂)_(n)—Ar group, wherein (CH₂)_(n)and Ar have the above meanings, or

R⁵ and R⁶ together with intervening atoms form an additional ring offormula (IV)

 wherein

Z stands for CH₂, C═O, C(NH), SO, SO₂, CH₂CO, COCH₂, CH₂CH₂CO. COCH₂CH₂or CH₂CH₂, and

X stands for hydrogen, C₁-C₃ alkyl, NH₂, amino-C₁-C₃ alkyl oramino-C₁-C₃ dialkyl or (CH₂)_(n)—Ar group, wherein (CH₂)_(n) and Ar havethe above meanings,

are obtained as follows:

Step 1:

The first step of the invention includes a reaction of6-O-methyl-9a-aza-9a-homo-erythromycin A or6-O-methyl-8a-aza-8a-homoerythromycin A, obtained according to PCT/HR99/00004, 4/99, with ethylene carbonate in the presence of inorganic ororganic bases, preferably potassium carbonate, in a reaction-inertsolvent, preferably in ethyl acetate, yielding corresponding11,12-cyclic carbonates of the general formula (I), wherein A stands forNH and B simultaneously stands for C═O group, or A stands for C═O groupand B simultaneously stands for NH group, R¹ stands for L-cladinosylgroup of formula (II) and R², R³ and R⁴ are mutually the same and standfor hydrogen, R⁵ and R⁶ together with intervening atoms form anadditional ring of formula (IVb), wherein Z stands for C═O group.

Step 2:

11,12-cyclic carbonates obtained in the Step 1, are subjected tohydrolysis with strong acids, preferably with 0.25-1.5 N hydrochloricacid, in a mixture of water and lower alcohols, preferably methanol,ethanol or isopropanol, over 10-30 hours at room temperature, yielding3-decladinosyl derivatives of general formula (I), wherein A stands forNH group and B simultaneously stands for C═O group, or A stands for C═Ogroup and B simultaneously stands for NH group, R¹ stands for OH group,R², R³ and R⁴ are mutually the same and stand for hydrogen, and R⁵ andR⁶ together with intervening atoms form an additional ring of formula(IVb), wherein Z stands for C═O group.

Step 3:

3-Decladinosyl derivatives from the Step 2 are subjected to a selectiveacylation of the hydroxyl group in 2′-position. Acylation is carried outwith chlorides or anhydrides of carboxylic acids with up to 4 carbonatoms, preferably with acetic acid anhydride, in the presence ofinorganic or organic bases, in a reaction-inert solvent at a temperaturefrom 0-30° C., yielding 2′-O-acyl derivatives of the general formula(I), wherein A stands for NH group and B simultaneously stands for C═Ogroup, or A stands for C═O group and B simultaneously stands for NHgroup, R¹ stands for OH group, R² and R⁴ are mutually the same and standfor hydrogen, R³ stands for acetyl and R⁵ and R⁶ together withintervening atoms form an additional ring of formula (IVb), wherein Zstands for C═O group.

As suitable bases sodium hydrogen carbonate, sodium carbonate, potassiumcarbonate, triethylamine, pyridine, tributylamine, preferably sodiumhydrogen carbonate are used. As a suitable inert solvent methylenechloride, dichloroethane, acetone, pyridine, ethyl acetate,tetrahydrofuran, preferably methylene chloride is used.

Step 4:

2′-Acetyl derivatives from the Step 3 are optionally subjected to areaction with mixed anhydrides of carboxylic acids of formula Y—COO—R¹,wherein Y stands for hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl group with atleast one incorporated O, N or S atom, or Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n is 1-10, without or withincorporated O, N or S atoms, and Ar stands for 5-10-membered monocyclicor bicyclic aromatic ring comprising 0-3 O, N or S atoms, which isunsubstituted or substituted with 1-3 groups representing halogen, OH,OMe, NO₂, NH₂, amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl, CN, SO₂NH₂,C₁-C₃ alkyl and R¹ is a group which is usually used for the preparationof mixed anhydrides such as pivaloyl, p-toluenesulfonyl,isobutoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl group, in thepresence of inorganic or organic bases, in a reaction-inert solvent,preferably in methylene chloride, at a temperature from 0-30° C. for3-100 hours, yielding 3-acyl derivatives of general formula (I), whereinR¹ stands for a group of formula (III), wherein Y has the abovemeanings, A stands for NH group and B simultaneously stands for C═Ogroup, or A stands for C═O group and B simultaneously stands for NHgroup, R² and R⁴ are mutually the same and stand for hydrogen. R³ standsfor acetyl and R⁵ and R⁶ together with intervening atoms form anadditional ring of formula (IVb), wherein Z stands for C═O group, whichare subsequently subjected to deprotection with lower alcohols,preferably in methanol, at a temperature from room temperature to thereflux temperature of the solvent, yielding a compound of the generalformula (I), wherein R³ stands for hydrogen and all remainingsubstituents have the above meanings.

Step 5:

2′-Acetyl derivatives from the Step 3 are optionally subjected tooxidation of the hydroxyl group in C-3 position of an aglycone ringaccording to a modified Moffat-Pfitzner process with N,N-dimethylaminopropyl-3-ethyl-carbodiimide in the presence of dimethyl sulfoxideand pyridinium trifluoroacetate as a catalyst in an inert organicsolvent, preferably in methylene chloride, at a temperature from 10° C.to room temperature, yielding 3-oxo derivatives of the general formula(I), wherein A stands for NH group and B simultaneously stands for C═Ogroup, or A stands for C═O group and B simultaneously stands for NHgroup, R¹ together with R² stands for ketone, R³ stands for acetyl, R⁴stands for hydrogen and R⁵ and R⁶ together with intervening atoms forman additional ring of formula (IVb), wherein Z stands for C═O group,which are subsequently subjected to deprotection in lower alcohols,preferably in methanol, at a temperature from room temperature to thereflux temperature of the solvent, yielding a compound of the generalformula (I), wherein R³ stands for hydrogen and all remainingsubstituents have the above meanings.

Step 6:

By subjecting 6-O-methyl-9a-aza-9a-homoerythromycin A or6-O-methyl-8a-aza-8a-homoerythromycin A obtained according to PCT/HR99/00004, 4/99, to hydrolysis with strong acids as described in the Step2, followed by a selective acylation of 2′-position as in the Step 3 andby a reaction with mixed anhydrides as in the Step 4, there are obtainedcompounds of the general formula (I), wherein R¹ has the meaning of agroup of the formula (III), wherein Y stands for hydrogen, C₁-C₆ alkyl,C₁-C₆ alkyl group with at least one incorporated O, N or S atom, or Ystands for (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyl and n standsfor 1-10, without or with incorporated O, N or S atoms, and Ar standsfor 5-10-membered monocyclic or bicyclic aromatic ring containing 0-3 O,N or S atoms, which is unsubstituted or substituted with 1-3 groupsrepresenting halogen, OH, OMe, NO₂, NH₂, amino-C₁-C₃-alkyl oramino-C₁-C₃ dialkyl, CN, SO₂NH₂, C₁-C₃ alkyl, R², R³, R⁴, and R⁶ aremutually the same and stand for hydrogen and R⁵ is OH group.

Step 7:

By subjecting 6-O-methyl-9a-aza-9a-homoerythromycin A or6-O-methyl-8a-aza-8a-homoerythromycin A obtained according to PCT/HR99/00004, 4/99, to hydrolysis with strong acids as described in the Step2, followed by a selective acylation of 2′-position as in the Step 3 andby oxidation and deprotection as in the Step 5, after purification withlow pressure chromatography on a silica gel column using the systemethyl acetate-(n-hexane)-diethyl amine 10:10:2 and by subsequentevaporation of chromatographically homogeneous fractions with lower Rfand rechromatography in the system CH₂Cl₂—CH₃OH-conc.NH₄OH 90:9:0.5,there is obtained a compound of the general formula (I), wherein Astands for NH group and B simultaneously stands for C═O group or Astands for C═O group and B simultaneously stands for NH group, R¹together with R² stands for a ketone, R³ and R⁶ are mutually the sameand stand for hydrogen and R⁴ together with R⁵ stands for a ketone.

Alternatively, compounds from the Step 4 can be obtained by subjectingthe compounds from the Step 6 to a reaction with ethylene carbonate in amanner as described in the Step 1.

Alternatively, the compounds from the Step 2 can be obtained by changingthe sequence of the reaction steps in such a manner that6-O-methyl-9a-aza-9a-homoerythromycin A or6-O-methyl-8a-aza-8a-homoerythromycin A obtained according to PCT/HR99/00004, 4/99, are first subjected to a hydrolysis with strong acids asdescribed in the Step 2 and then to a reaction with ethylene carbonatein a manner described in the Step 1.

Alternatively, the compounds of the Step 5 can be obtained in such amanner that 3-decladinosyl-3-oxo-6-O-methyl-9a-aza-9a-homoerythromycin Aor 3-decladinosyl-3-oxo-6-O-methyl-8a-aza-8a-homo-erythromycin Aobtained according to PCT/HR 99/00004, 4/99, are subjected to a reactionwith ethylene carbonate in the manner described in the Step 1.

Pharmaceutically acceptable addition salts which are also an object ofthe present invention, are obtained by a reaction of novel compoundsfrom the class of 6-O-methyl-9a-aza-9a-homo- and6-O-methyl-8a-aza-8a-homo-erythromycins A of the general formula (I),wherein A, B, R¹, R², R³, R⁴, R⁵ and R⁶ have the above meanings, with anat least equimolar amount of a suitable corresponding inorganic ororganic acid such as hydrochloric, hydroiodic, sulfuric, phosphoric,acetic, propionic, trifluoroacetic, maleic, citric, stearic, succinic,ethylsuccinic, methanesulfonic, benzenesulfonic, p-toluenesulfonic,laurylsulfonic acid and the like, in a reaction-inert solvent. Additionsalts are isolated by filtration if they are insoluble in thereaction-inert solvent, by precipitation by means of a non-solvent or byevaporation of the solvent, most frequently by lyophilization.

The process is illustrated by the following examples which do not limitthe scope of the invention in any way.

EXAMPLE 1 6-O-Methyl-9a-aza-9a-homoerythromycin A 11,12-Cyclic Carbonate

To ethyl acetate (80 ml) 6-O-methyl-9a-aza-9a-homoerythromycin A (3 g,0.0039 mole) obtained according PCT/HR 99/00004, 4/99, K₂CO₃ (9 g,0.0651 mole) and ethylene carbonate (9 g, 0.1022 mole) were added andthen the reaction mixture was stirred under heating at refluxtemperature for 12 hours. The reaction suspension was diluted with ethylacetate (100 ml) and rinsed with saturated NaCl solution (100 ml) andwater (200 ml). The evaporation of the organic solvent gave an oilyresidue, from which by low-pressure chromatography on a silica gelcolumn using the system CH₂Cl₂—CH₃OH-conc.NH₄OH, 90:9:1.5 the titleproduct (2 g) was obtained.

IR (KBr) cm⁻¹ 3452, 2974, 2939, 2833, 2787, 1815, 1737, 1668, 1531,1456, 1379, 1287, 1168, 1111, 1053, 1014, 955, 903. ¹H NMR (300 MHz,CDCl₃) δ 5.76 (9a-CONH), 5.10 (H-1″), 4.87 (H-13), 4.41 (H-1′), 4.31(H-10), 4.20 (H-11), 4.03 (H-5″), 3.97 (H-3), 3.65 (H-5), 3.47 (H-5′),3.34 (3″-OCH₃), 3.18 (H-2′), 3.14 (6-OCH₃), 3.02 (H-4″), 2.84 (H-2),2.43 (H-3′), 2.33 (H-2″a), 2.28/3′-N(CH₃)₂/, 2.19 (H-8), 2.28 (H-7a),2.19 (H-4), 1.79 (H-14a), 1.65 (H-4′a), 1.57 (H-2″b), 1.56 (H-14b), 1.49(12-CH₃), 1.38 (6-CH₃), 1.29 (5″-CH₃), 1.27 (H-7b), 1.24 (3″-CH₃), 1.21(5′-CH₃), 1.20 (H-4′b), 1.20 (2-CH₃), 1.18 (10-CH₃), 1.07 (4-CH₃), 1.06(8-CH₃), 0.90 (15-CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 178.4 (C-9), 177.2(C-1), 153.9 (C═O carbonate), 102.7 (C-1′), 94.0 (C-1″), 84.7 (C-12),83.6 (C-11), 79.1 (C-5), 78.7 (C-6), 77.9 (C-4″), 75.5 (C-3), 75.2(C-13), 72.6 (C-3″), 70.7 (C-2′), 68.5 (C-5′), 65.3 (C-5″), 65.1 (C-3′),51.0 (6-OCH₃), 49.2 (3″-OCH₃), 44.9 (C-2), 44.3 (C-10), 42.0 (C-4),40.1/3′-N(CH₃)₂/, 39.4 (C-7), 36.2 (C-8), 34.3 (C-2″), 28.6 (C-4′), 21.8(C-14), 21.3 (3″-CH₃), 21.1 (5′-CH₃), 21.0 (6-CH₃), 19.6 (8-CH₃), 18.0(5″-CH₃), 14.1 (2-CH₃), 13.0 (10-CH₃), 12.8 (12-CH₃), 10.2 (15-CH₃), 9.1(4-CH₃).

EXAMPLE 2 3-Decladinosyl-3-oxy-6-O-methyl-9a-aza-9a-homoerythromycin A11,12-Cyclic Carbonate

In 0.25 N hydrochloric acid (45 ml) the substance from the Example 1(1.5 g, 0.002 mole) was dissolved and it was left standing at roomtemperature for 48 hours. Onto the reaction mixture CH₂Cl₂ (30 ml, pH1.5) was added, the pH of the mixture was adjusted with conc. NH₄OH topH 9.0, the layers were separated and the aqueous one was extracted twomore times with CH₂Cl₂ (30 ml). The combined organic extracts wererinsed with 10% aqueous NaHCO₃ solution and water and evaporated,yielding 3-decladinosyl-3-oxy-6-O-methyl-9a-aza-9a-homoerythromycin A11,12-cyclic carbonate (1.1 g)

IR (KBr) cm⁻¹ 3440, 2974, 2939, 1822, 1729, 1650, 1525, 1457, 1380,1241, 1167, 1113, 1073, 1047, 983. FAB-MS m/z 731 (MH⁺).

EXAMPLE 32′-O-Acetyl-3-decladinosyl-3-oxy-6-O-methyl-9a-aza-9a-homoerythromycin A11,12-Cyclic Carbonate

To a solution of3-decladinosyl-3-oxy-6-O-methyl-9a-aza-9a-homoerythromycin A11,12-cyclic carbonate from the Example 2 (1.0 g, 0.0016 mole) in CH₂Cl₂(100 ml), NaHCO₃ (0.62 g, 0.0074 mole) and acetic acid anhydride (0.36ml, 0.0038 mole) were added and it was then stirred for 4 hours at roomtemperature. Onto the reaction mixture a saturated NaHCO₃ solution (50ml) was added, the layers were separated and the aqueous one wasextracted two more times with CH₂Cl₂ (20 ml). The combined organicextracts were rinsed with a saturated NaHCO₃ solution and water andevaporated, yielding the title product (1.15 g) with the followingphysical-chemical constants:

IR (KBr) cm⁻¹ 3444, 2975, 2936, 1816, 1737, 1666, 1539, 1461, 1376,1237, 1166, 1113, 1046, 1015, 985, 943. ¹H NMR (300 MHz, CDCl₃) δ 6.97(9a-CONS), 4.97 (H-13), 4.80 (H-2′), 4.69 (H-1′), 4.29 (H-11), 4.27(H-10), 3.89 (H-5), 3.62 (H-3), 3.53 (H-5′), 3.22 (6-OCH₃), 2.87 (H-3′),2.74 (H-2), 2.30/3′-N(CH₃)₂/, 2.30 (H-8), 1.98 (H-4), 1.81 (H-7a), 1.86(H-14a), 1.78 (H-4′a), 1.64 (H-14b), 1.41*(12-CH₃), 1.35 (H-4′b), 1.30(2-CH₃), 1.30 (H-7b), 1.29*(6-CH₃), 1.26 (5′-CH₃), 1.19 (10-CH₃), 1.12(8-CH₃), 0.94 (4-CH₃), 0.92 (15-CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 178.4(C-1)*, 177.2 (C-9)*, 170.0 (2′-COCH₃), 153.3 (C═O carbonate), 99.3(C-1′), 85.5 (C-12), 83.8 (C-11), 79.6 (C-6), 78.8 (C-5), 76.9 (C-13),76.5 (C-3), 70.9 (C-2′), 68.5 (C-5′), 62.5 (C-3′), 50.2 (6-OCH₃), 43.9(C-2), 43.8 (C-10), 39.9/3′-N(CH₃)₂/, 38.9 (C-7), 36.7 (C-4), 34.1(C-8), 30.8 (C-4′), 21.7 (C-14), 20.8 (5′-CH₃), 21.1 (2′-CONH₃), 19.1(6-CH₃), 18.1 (8-CH₃), 17.5 (10-CH₃), 15.4 (2-CH₃), 12.2 (12-CH₃), 10.0(15-CH₃), 7.7 (4-CH₃).

EXAMPLE 4 3-Decladinosyl-3-oxo-6-O-methyl-9a-aza-9a-homoerythromycin A11,12-Cyclic Carbonate

To a solution of2′-O-acetyl-3-decladinosyl-3-oxy-6-O-methyl-9a-aza-9a-homo-erythromycinA 11,12-cyclic carbonate from the Example 3 (1 g, 0.0015 mole) in CH₂Cl₂(20 ml), dimethyl sulfoxide (2.5 ml) andN,N-dimethyl-aminopropyl-ethyl-carbodiimide (2.64 g, 0.014 mole) wereadded. The reaction mixture was cooled to 15° C. and then, understirring and maintaining the temperature, a pyridinium trifluoroacetatesolution (2.7 g, 0.014 mole) in CH₂Cl₂ (12 ml) was gradually added dropby drop during 1 hour. The temperature of the reaction mixture wasgradually raised to room temperature, it was kept stirring for further 4hours and the reaction was ceased by the addition of a saturated NaClsolution (20 ml) and CH₂Cl₂ (20 ml). After alkalizing to pH 9.5 (2NNaOH), the reaction mixture was extracted with CH₂Cl₂ and the organicextracts were rinsed with a saturated NaCl solution and water and driedover K₂CO₃. After filtration and evaporation of methylene chloride at areduced pressure, an oily residue was obtained, which was subjected tomethanolysis (70 ml) for 24 hours at room temperature. Methanol wasevaporated at a reduced pressure and the obtained residue was purifiedby low-pressure chromatography on a silica gel column using chloroformand then the solvent system CHCl₃—CH₃OH-conc.NH₄OH, 6:1:0.1. Byevaporation of chromatographically homogeneous fractions, the titleproduct (0.2 g) with the following physical-chemical constants wasobtained:

IR (KBr) cm⁻¹ 3442, 3380, 2975, 2940, 2881, 2840, 2787, 1813, 1750,1717, 1666, 1586, 1526, 1458, 1381, 1325, 1237, 1166, 1111, 1079, 1050,1017, 991, 957. ¹H NMR (300 MHz, CDCl₃) δ 6.39 (9a-CONH), 4.96 (H-13),4.44 (H-1′), 4.34 (H-10), 4.21 (H-11), 4.14 (H-5), 3.94 (H-2), 3.60(H-5′), 3.27 (H-4), 3.20 (H-2′), 2.85 (6-OCH₃), 2.50 (H-3′),2.27/3′-N(CH₃)₂/, 2.27 (H-8), 2.27 (H-7a), 1.84 (H-14a), 1.67 (H-4′a),1.62 (H-14b), 1.52 (6-CH₃), 1.45 (2-CH₃), 1.45 (H-7b), 1.34 (4-CH₃),1.27 (12-CH₃), 1.24 (5′-CH₃), 1.23 (H-4′b), 1.22 (10-CH₃), 1.12 (8-CH₃),0.91 (15-CH₃). ¹³C NMR (75 MHz, CDCl₃) δ 206.7 (C-3), 177.0 (C-9)*,170.1*(C-1), 153.6 (C═O carbonate), 103.4 (C-1′), 84.4 (C-12), 84.1(C-11), 78.5 (C-5), 78.1 (C-6), 75.7 (C-13), 70.1 (C-2′), 69.2 (C-5′),65.4 (C-3′), 50.1 (6-OCH₃), 50.0 (C-2), 47.7 (C-4), 44.2 (C-10),39.9/3′-N(CH₃)₂/, 39.1 (C-7), 36.2 (C-8), 28.0 (C-4′), 21.7 (C-14), 20.9(5′-CH), 20.5 (12-CH₃), 19.8 (8-CH₃), 16.3 (2-CH₃), 14.8 (4-CH₃), 13.6(10-CH₃), 13.0 (6-CH₃), 10.0 (15-CH₃).

EXAMPLE 5 3-Decladinosyl-3-oxy-6-O-methyl-9a-aza-9a-homoerythromycin A11,12-Cyclic Carbonate

By a reaction of3-decladinosyl-3-oxy-6-O-methyl-9a-aza-9a-homoerythromycin A andethylene carbonate according to the process described in the Example 1,3-decladinosyl-3-oxy-6-O-methyl-9a-aza-9a-homoerythromycin A11,12-cyclic carbonate with the physical-chemical constants as given inthe Example 2 was obtained.

EXAMPLE 63-Decladinosyl-3-O-(4-nitrophenyl)acetyl-6-O-methyl-9a-aza-9a-homoerythromycinA 11,12-Cyclic Carbonate

To a solution of 4-nitrophenyl acetic acid (0.263 g, 0.0015 mole) in dryCH₂Cl₂ (5 ml), triethylamine (0.202 ml, 0.0015 mole) was added and itwas cooled to 0° C. To the reaction mixture pivaloyl chloride (0.180 ml,0.0015 mole) was added, it was stirred for 30 minutes at the sametemperature and then pyridine (0.4 ml) and a solution of2′-O-acetyl-3-decladinosyl-3-oxy-6-O-methyl-9a-aza-9a-homoerythromycin A11,12-cyclic carbonate from the Example 3 (0.3 g, 0.0004 mole) wereadded. It was stirred at the same temperature for further 3 hours, tothe reaction mixture a saturated NaCl solution (20 ml) was added, thelayers were separated and the aqueous one was extracted two more timeswith CH₂Cl₂ (20 ml). The combined organic extracts were dried over K₂CO₃and evaporated at a reduced pressure. Onto the oily residue methanol (30ml) was added and it was left standing at room temperature over night.Methanol was evaporated at a reduced pressure and the obtained residuewas purified by chromatography on a silica gel column using the systemCH₂Cl₂—CH₃OH-conc.NH₄OH, 90:4:0.5 and by crystallisation from a mixturemethylene chloride-ether-(n-hexane), whereby a chromatographicallyhomogeneous title product was obtained.

IR (KBr) cm⁻¹ 3417, 3380, 2975, 2939, 1813, 1750, 1742, 1669, 1524,1526, 1458, 1348, 1167, 1076, 1046.

EXAMPLE 73-Decladinosyl-3-O-(4-nitrophenyl)acetyl-6-O-methyl-9a-aza-9a-homoerythromycinA

By reacting2′-O-acetyl-3-decladinosyl-3-oxy-6-O-methyl-9a-aza-9a-homoerythromycin A(0.3 g, 0.0004 mole) obtained according to the process described inPCT/HR 99/00004, 4/99, 4-nitrophenyl acetic acid (0.263 g, 0.0015 mole)and pivaloyl chloride (0.180 ml, 0.015 mole), there was obtainedaccording to the process described in the Example 6, achromatographically homogeneous title product with the followingphysical-chemical constants:

IR (KBr) cm⁻¹ 3396, 2976, 2941, 2879, 2791, 1732, 1698, 1669, 1601,1521, 1456, 1380, 1346, 1232, 1182, 1111, 1073, 1051, 983. FAB-MS m/z768 (MH⁺).

EXAMPLE 83-Decladinosyl-3,11-dioxo-6-O-methyl-9a-aza-9a-homoerythromycin A

To a solution of2′-O-acetyl-3-decladinosyl-3-oxy-6-O-methyl-9a-aza-9a-homoerythromycin A(0.760 g, 0.0012 mole) obtained according to the process described inPCT/HR 99/00004, 4/99, in CH₂Cl₂ (25 ml), dimethyl sulfoxide (2.5 ml)and N,N-dimethyl-aminopropyl-ethyl-carbodiimide (2.7 g, 0.014 mole) wereadded. The reaction mixture was cooled to 15° C. and then, understirring and maintaining the temperature, gradually drop by drop asolution of pyridinium trifluoroacetate (2.75 g, 0.0014 mole) in CH₂Cl₂(10 ml) was added over 45 minutes. The temperature of the reactionmixture was gradually raised to room temperature, the mixture wasstirred for further 10 hours and then the reaction was ceased by theaddition of a saturated NaCl solution (25 ml) and CH₂Cl₂ (25 ml). Afteralkalizing with 2 N NaOH to pH 9.5, the reaction mixture was extractedwith CH₂Cl₂, the organic extracts were subsequently rinsed with asaturated NaCl solution, NaHCO₃ and water and dried over K₂CO₃. Afterfiltration and evaporation of CH₂Cl₂ at a reduced pressure, a product(1.2 g) was obtained. The oily residue was subjected to methanolysis (50ml) for 24 hours at room temperature. Methanol was evaporated at areduced pressure and the obtained residue was purified by low-pressurechromatography on a silica gel column using the system ethylacetate-(n-hexane)-diethyl amine, 10:10:2. By evaporation ofchromatographically homogeneous fractions with lower Rf and byrechromatography in the system CH₂Cl₂—CH₃OH-conc.NH₄OH, 90:9:0.5, achromatographically homogeneous title product with the followingphysical-chemical constants was obtained:

IR (KBr) cm⁻¹ 3291, 2975, 2940. 2879, 2788, 1732, 1715. 1661. 1557,1457, 1378, 1339, 1300, 1264, 1174, 1110, 1079, 1051, 1010, 982. ¹HNMR(300 MHz, CDCl₃) δ 7.57 (9a-CONH), 5.05 (H-10), 4.85 (H-13), 4.62(H-5), 4.35 (H-1′), 3.77 (H-2), 3.65 (H-5′), 3.47 (H-4), 3.23 (H-2′),3.09 (6-OCH_(3),) 2.57 (H-8), 2.57 (H-7a), 2.50 (H-3′),2.28/3′-N(CH₃)₂/, 2.02 (H-14a), 1.72 (10-CH₃), 1.70 (H-4′a), 1.58(H-14b), 1.43 (H-7b), 1.38 (4-CH₃), 1.33*(6-CH₃), 1.31 (2-CH₃), 1.28(5′-CH₃), 1.22*(12-CH₃), 1.21 (H-4′b), 1.11 (8-CH₃), 0.89 (15-CH₃). ¹³CNMR (75 MHz, CDCl₃) δ 211.0 (C-11), 208.5 (C-3), 179.0 (C-9)*,172.4*(C-1), 102.8 (C-1′), 79.6*(C-12), 79.1 (C-6), 76.7 (C-13), 73.8(C-5), 70.0 (C-2′), 69.1 (C-5′), 65.5 (C-3′), 53.6 (C-10) 49.2 (6-OCH₃),48.5 (C-2), 44.9 (C-4), 40.0/3′N(CH₃)₂/, 38.8 (C-7), 32.7 (C-8), 28.2(C-4′), 21.1 (5′-CH₃), 20.4 (C-14), 18.8**(12-CH₃), 18.6**(6-CH₃), 17.7(8-CH₃), 16.1 (10-CH₃), 14.3 (4-CH₃), 13.3 (2-CH₃), 10.5-CH₃). FAB-MSm/z 601 (MH⁺).

EXAMPLE 9 3-Decladinosyl-3-oxy-6-O-methyl-8a-aza-8a-homoerythromycin A11,12-Cyclic Carbonate

To ethyl acetate (15 ml) there were added3-decladinosyl-3-oxy-6-O-methyl-8a-aza-8a-homoerythromycin A (1.9 g,0.0031 mole) obtained according to the process described in PCT/HR99/00004, 4/99, K₂CO₃ (2.5 g, 0.0018 mole) and ethylene carbonate (5.5g, 0.063 mole), and then the reaction mixture was stirred for 10 hoursat the temperature 90° C. To the reaction mixture again ethylenecarbonate (2.5 g) was added and it was stirred for further 7 hours atthe same temperature. Into the cooled reaction mixture water (30 ml) wasadded, the layers were separated and the aqueous one was extracted withCH₂Cl₂ (2×30 ml). The combined organic extracts were dried over K₂CO₃and evaporated under reduced pressure, yielding a crude residue (2.5 g).By chromatography on a silica gel column using the systemCH₂Cl₂—CH₃OH-conc.NH₄OH, 90:4:0.5, a chromatographically homogenoustitle product (1.3 g) was obtained.

IR (KBr) cm⁻¹ 3444, 2975, 2940, 2833, 1817, 1733, 1651, 1545, 1461,1384, 1340, 1235, 1165, 1111, 1082, 1049. ¹H NMR (600 MHz, CDCl₃) δ 5.90(8a-CONH), 5.27 (H-13), 4.53 (H-11), 4.40 (H-1′), 3.99 (H-3), 3.88(H-5), 3.77 (H-8), 3.55 (H-5′), 3.24 (H-2′), 3.12 (6-OCH₃), 2.60 (H-2),2.51 (H-10), 2.49 (H-3′), 2.26/3′-N(CH₃)₂/, 1.76 (H-14a), 1.70 (H-7a),1.67 (H-4′a), 1.67 (H-14b), 1.65 (H-7b), 1.61 (H-4), 1.37 (12-CH₃), 1.34(10-CH₃), 1.32 (6-CH₃), 1.30 (2-CH₃), 1.29 (8-CH₃), 1.26 (5′-CH₃), 1.25(H-4′b), 1.01 (4-CH₃), 0.93 (15-CH₃). ¹³C NMR (150 MHz, CDCl₃) δ 175.5(C-1), 170.4 (C-9), 153.1 (C═O carbonate), 106.9 (C-1′), 91.7 (C-5),86.8 (C-12), 82.9 (C-11), 79.1 (C-6), 76.8 (C-3), 74.8 (C-13), 70.4(C-2′), 69.8 (C-5′), 65.5 (C-3′), 49.3 (6-OCH₃), 43.9 (C-2), 43.8 (C-8),42.5 (C-10), 41.1 (C-7), 40.2/3′-N(CH₃)₂/, 37.1 (C-4), 28.1 (C-4′), 22.2(C-14), 21.7 (8-CH₃), 21.3 (6-CH₃), 20.8 (5′-CH₃), 16.3 (12-CH₃), 15.6(2-CH₃), 14.8 (10-CH₃), 10.2 (15-CH₃), 7.9 (4-CH₃). FAB-MS m/z 631(MH⁺).

EXAMPLE 102′-O-Acetyl-3-decladinosyl-3-oxy-6-O-methyl-8a-aza-8a-homoerythromycin A11,12-Cyclic Carbonate

To a mixture of solvents CH₂Cl₂ (10 ml) and acetone (1 ml),3-decladinosyl-3-oxy-6-O-methyl-8a-aza-8a-homoerythromycin A11,12-cyclic carbonate (0.75 g, 0.0012 mole) from the Example 9, NaHCO₃(0.5 g, 0.0059 mole) and acetic acid anhydride (0.28 ml, 0.003 mole)were added and it was stirred for 3 hours at room temperature. To thereaction mixture a saturated NaHCO₃ solution (10 ml) was added, thelayers were separated and the aqueous layer was extracted with CH₂Cl₂(2×20 ml). The combined organic extracts were rinsed with a saturatedNaCl solution, dried over K₂CO₃ and evaporated at a reduced pressure,yielding the title product (0.8 g).

IR (KBr) cm⁻¹ 3389, 2975, 2940, 1813, 1741, 1659, 1540, 1458, 1374,1237, 1166, 1058. ¹H NMR (600 MHz, CDCl₃) δ 6.22 (8a-CONH), 5.16 (H-13),4.78 (H-2′), 4.63 (H-1′), 4.53 (H-11), 3.89 (H-8), 3.84 (H-5), 3.83(H-3), 3.54 (H-5′), 3.13 (6-OCH₃), 2.87 (H-3′), 2.61 (H-2), 2.49 (H-10),2.30/3′-N(CH₃)₂/, 2.09 (COCH₃), 1.82 (H-14a), 1.80 )H-7a), 1.78 (H-4′a),1.75 (H-4), 1.64 (H-14b), 1.60 (H-7b), 1.39 (12-CH₃), 1.36 (H-4′b), 1.32(10-CH₃), 1.28 (2-CH₃), 1.26 (6-CH₃), 1.26 (5′-CH₃), 1.23 (8-CH₃), 0.92(15-CH₃), 0.91 (4-CH₃). ¹³C NMR (150 MHz, CDCl₃) δ 174.7 (C-1), 170.6(C-9), 170.3 (COCH₃), 153.2 (C═O carbonate), 101.5 (C-1′), 86.3 (C-5),85.5 (C-12), 82.4 (C-11), 78.6 (C-6), 76.0 (C-3), 75.5 (C-13), 71.3(C-2′), 68.8 (C-5′), 63.0 (C-3′), 49.9 (6-OCH₃), 43.8 (C, 2), 42.5(C-8), 42.4 (C-10), 41.1 (C-7), 40.0/3′-N(CH₃)₂/, 37.7 (C-4), 30.5(C-4′), 22.1 (C-8), 22.1 (C-14), 21.4 (6-CH₃), 21.2 (COCH₃), 21.0(5′-CH₃), 15.7 (12-CH₃), 15.3 (2-CH₃), 13.9 (10-CH₃), 10.1 (4-CH₃), 8.2(15-CH₃).

EXAMPLE 113-Decladinosyl-3-O-(4-nitrophenyl)acetyl-6-O-methyl-8a-aza-8a-homoerythromycinA 11,12-Cyclic Carbonate

By reacting2′-O-acetyl-3-decladinosyl-3-oxy-6-O-methyl-8a-aza-8a-homo-erythromycinA 11,12-cyclic carbonate (0.3 g, 0.0004 mole) obtained according to theprocess described in the Example 10,4-nitrophenyl acetic acid (0.263 g,0.0015 mole) and pivaloyl chloride (0.180 ml, 0.0015 mole), according tothe process described in the Example 6, a chromatographicallyhomogeneous title product with the following physical-chemical constantswas obtained:

IR (KBr) cm⁻¹ 3437, 2976, 2940, 1809, 1666, 1524, 1459, 1348, 1233,1166, 1111. ¹H NMR (600 MHz, CDCl₃) δ 8.20 and 7.52 (Ph), 6.19(8a-CONH), 5.47 (H-3), 5.01 (H-13), 4.47 (H-11), 4.05 (H-1′), 3.92(H-8), 3.84 and 3.80 (PhCH₂), 3.74 (H-5), 3.30 (H-5′), 3.20 (6-OCH₃),3.16 (H-2′), 2.83 (H-2), 2.48 (H-10), 2.38 (H-3′), 2.28/3′-N(CH₃)₂/,2.09 (COCH₃), 2.07 (H-4), 1.86 (H-14a), 1.83 (H-7a), 1.63 (H-4′a), 1.61(H-14b), 1.55 (H-7b), 1.44 (12-CH₃), 1.31 (10-CH₃), 1.30 (6-CH₃), 1.19(H-4′b), 1.20 (5′-CH₃), 1.24 (8-CH₃), 1.02 (2-CH₃), 0.91 (15-CH₃), 0.8(4-CH₃). ¹³C NMR (150 MHz, CDCl₃) δ 173.5*(C-1), 170.8*(C-9),169.8*(3-OCOCH₂—), 153.1 (C═O carbonate), 147.2, 141.2, 130.5, 123.7(Ph), 103.9 (C-1′). 85.9 (C-12), 82.4 (C-5), 82.0 (C-11), 79.0 (C-6),76.7 (C-3), 76.0 (C-13), 70.3 (C-2′), 69.6 (C-5′), 65.9 (C-3′), 50.7(6-OCH₃), 43.8 (C-2), 43.1 (C-10), 43.0 (C-8), 41.7 CH₂Ph),40.3/3′-N(CH₃)₂/, 38.4 (C-4), 28.3 (C-4′), 22.3 (8-CH₃), 22.3 (C-14),21.3 (6-CH₃), 21.1 (5′-CH₃), 15.0 (12-CH₃), 14.2 (2-CH₃), 13.8 (10-CH₃),10.6 (4-CH₃), 10.2 (15-CH₃). FAB-MS m/z 794 (MH⁺).

EXAMPLE 123-Decladinosyl-3-O-(4-nitrophenyl)acetyl-6-O-methyl-8a-aza-8a-homoerythromycinA

By reacting2′-O-acetyl-3-decladinosyl-3-oxy-6-O-methyl-8a-aza-8a-homoerythromycin A(0.3 g, 0.0004 mole) obtained according to the process described inPCT/HR 99/00004, 4/99, 4-nitrophenyl acetic acid (0.263 g, 0.0015 mole),pivaloyl chloride (0.180 ml, 0.0015 mole) and triethylamine (0.202 ml,0.0015 mole), according to the process described in the Example 6, achromatographically homogeneous title product with the followingphysical-chemical constants was obtained:

IR (KBr) cm⁻¹ 3440, 2976, 2937, 1741, 1651, 1525, 1461, 1348, 1168,1076, 1050. FAB-MS m/z 768 (MH⁺). ¹H NMR (600 MHz, CDCl₃) δ 8.20 (d,Ph), 7.54 (Ph), 5.91 (8a-CONH), 5.38 (H-3), 5.03 (H-13), 3.96 (H-1′),3.87 (PhCH₂), 3.82 (H-8), 3.81 (PhCH₂), 3.74 (H-5), 3.42 (H-11), 3.25(H-5′), 3.19 (H-2′), 3.19 (6-OMe), 2.77 (H-2), 2.38 (H-10), 2.33 (H-3′),2.27/3′-N(CH₃)₂/, 2.14 (H-4), 1.92 (H-14a), 1.86 (H-7a), 1.60 (H-4′a),1.51 (H-7b), 1.47 (H- 14b), 1.29 (6-CH₃), 1.24 (8-CH₃), 1.19 (10-CH₃),1.19 (H-4′b), 1.18 (5′-CH₃), 1.13 (4-CH₃), 1.10 (12-CH₃), 0.92 (2-CH₃),0.84 (15-CH₃). ¹³C NMR (150 MHz, CDCl₃) δ 174.9 (C-9), 174.7 (C-1),169.7 (3-OCOCH₂—), 147.2, 141.1, 130.4, 123.7 (Ph), 104.1 (C-1′), 83.3(C-5), 78.7 (C-3), 78.6 (C-13), 77.5 (C-6), 74.8 (C-12), 70.5 (C-11),70.4 (C-2′), 69.6 (C-5′), 66.1 (C-3′), 51.0 (6-OCH₃), 43.2 (C-2), 42.9(C-10), 42.6 (C-8), 42.2 (C-7), 41.3 (-CH₂Ph), 40.3/3′-N(CH₃)₂/, 37.1(C-4), 28.3 (C-4′), 23.1 (8-CH₃), 21.3 (C-14), 21.1 (5′-CH₃), 20.9(6-CH₃), 16.3 (12-CH₃), 15.6 (2-CH₃), 10.8 (15-CH₃), 10.1 (10-CH₃), 9.53(4-CH₃).

EXAMPLE 133-Decladinosyl-3-O-(4-chlorophenyl)acetyl-6-O-methyl-8a-aza-8a-homoerythromycinA 11,12-Cyclic Carbonate

By reacting2′-O-acetyl-3-decladinosyl-3-oxy-6-O-methyl-8a-aza-8a-homoerythromycin A11,12-cyclic carbonate (0.2 g, 0.0003 mole) obtained according to theprocess described in the Example 10, 4-chlorophenyl acetic acid (0.330g, 0.0019 mole), pivaloyl chloride (0.239 ml, 0.0019 mole) and triethylamine (0.270 ml, 0.0019 mole) over 3 days at room temperature accordingto the process described in the Example 6, a chromatographicallyhomogenous title product with the following physical-chemical constantswas obtained:

IR (KBr) cm⁻¹ 3388, 2976, 2941, 2883, 2787, 1812, 1744, 1667, 1541,1493, 1458, 1380, 1357, 1332, 1234, 1165, 1111, 1051, 1017, 981. FAB-MSm/z 783 (MH⁺).

EXAMPLE 143-Decladinosyl-3-O-(4-methoxyphenyl)acetyl-6-O-methyl-8a-aza-8a-homoerythromycinA

By reacting2′-O-acetyl-3-decladinosyl-3-oxy-6-O-methyl-8a-aza-8a-homoerythromycin A(0.250 g, 0.0004 mole) obtained according to the process described inPCT/HR 99/00004, 4/99, 4-methoxyphenyl acetic acid (0.321 g, 0.0019mole), pivaloyl chloride (0.239 ml, 0.0019 mole) and triethylamine(0.270 ml, 0.0019 mole) over 5 days at room temperature according to theprocess described in the Example 6, a chromatographically homogeneoustitle product was obtained:

IR (KBr) cm⁻¹ 3444, 2975, 2939, 2836, 2787, 1740, 1651, 1514, 1462,1379, 1337, 1257, 1167, 1110, 1076, 1035, 984, 959. FAB-MS m/z 753(MH⁺).

EXAMPLE 15 3-Decladinosyl-3-oxo-6-O-methyl-8a-aza-8a-homoerythromycin A11,12-Cyclic Carbonate

To a solution of2′-O-acetyl-3-decladinosyl-3-oxy-6-O-methyl-8a-aza-8a-homoerythromycin A11,12-cyclic carbonate from the Example 10 (0.4 g, 0.00059 mole) inCH₂Cl₂ (20 ml) dimethyl sulfoxide (0.7 ml) andN,N-dimethyl-aminopropyl-ethyl-carbodiimide (0.7 g, 0.0036 mole) wereadded. The reaction mixture was cooled to 15° C., under stirring andmaintaining the temperature a solution of pyridinum trifluoroacetate(0.7 g, 0.0036 mole) in CH₂Cl₂ (5 ml) was added drop by drop over 15minutes, the temperature of the reaction mixture was raised to roomtemperature and the reaction was kept stirring over night. After theaddition of a saturated NaCl solution (30 ml) and CH₂Cl₂ (30 ml), thereaction mixture was alkalized to pH 10 (2 N NaOH) and extracted withCH₂Cl₂. The organic extracts were rinsed with a saturated NaCl solutionand water, dried over K₂CO₃ and evaporated at a reduced pressure,yielding 0,5 g of an oily residue, which was subjected to methanolysis(30 ml) at room temperature for 24 hours. Methanol was evaporated at areduced pressure, the obtained residue (0.49 g) was purified bylow-pressure chromatography on a silica gel column using chloroform andthen solvent system CH₂Cl₂—CH₃OH-conc.NH₄OH, 90:4:0.5 yielding achromatographically homogeneous title product with the followingphysical-chemical constants:

IR (KBr) cm⁻¹ 3379, 2976, 1814, 1755, 1713, 1668, 1539, 1457, 1381,1243, 1166, 1110, 1062, 995. FAB-MS m/z 629 (MH⁺).

What is claimed is:
 1. A compound of formula (I),

or its pharmaceutically acceptable addition salts with inorganic ororganic acids or hydrates thereof, wherein A stands for NH group and Bsimultaneously stands for C═O group, or A stands for C═O group and Bsimultaneously stands for NH group, R¹ stands for OH group, L-cladinosylgroup of formula (II),

R¹ stands for a group of formula (III),

 wherein Y stands for hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl group with atleast one incorporated O, N or S atom or Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n is 1-10, with or withoutincorporated O, N or S atoms, and Ar stands for a 5-10-memberedmonocyclic or bicyclic aromatic ring containing 0-3 O, N or S atoms,which is unsubstituted or substituted with 1-3 groups representinghalogen, OH, OMe, NO₂, NH₂, amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl,CN, SO₂NH₂, C₁-C₃ alkyl, or R¹ together with R² stands for oxo, R²stands for hydrogen or together with R¹ stands for oxo, R³ stands forhydrogen or C₁-C₄ alkanoyl group, R⁴ stands for hydrogen or togetherwith R⁵ stands for oxo, R⁵ stands for OH, NH₂, amino-C₁-C₃ alkyl oramino-C₁-C₃ dialkyl, O(CH₂)_(n)Ar or S(CH₂)_(n)Ar, wherein (CH₂)_(n) andAr have the above meanings, or together with R⁴ stands for oxo, withproviso that when R⁵ stands for OH, R¹ does not stand for L-cladinosylgroup of formula (II) or OH, R⁶ stands for hydrogen, C₁-C₆ alkyl, heteroC₁-C₆ alkyl group wherein said hetero atom is O, N or S, or (CH₂)_(n)—Argroup, wherein (CH₂)_(n) and Ar have the above meanings, with provisothat when R⁶ stands for H, R¹ does not stand for L-cladinosyl group offormula (II) or OH, or R⁵ and R⁶ together with intervening atoms form anadditional ring of formula (IV)

 wherein Z stands for CH₂, C═O, C(NH), SO, SO₂, CH₂CO, COCH₂, CH₂CH₂CO,COCH₂CH₂ or CH₂CH₂, and X stands for hydrogen, C₁-C₃ alkyl, NH₂,amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl or (CH₂)_(n)—Ar group, wherein(CH₂)_(n) and Ar have the above meanings.
 2. A compound according toclaim 1, characterized in that A stands for NH and B simultaneouslystands for C═O group, R¹ stands for L-cladinosyl group of formula (II)and R², R³ and R⁴ are mutually the same and stand for hydrogen, R⁵ andR⁶ together with intervening atoms form an additional ring of formula(IV), wherein Z stands for CH₂, C═O, C(NH), SO, SO₂, CH₂CO, COCH₂,CH₂CH₂CO, COCH₂CH₂ or CH₂CH₂, and X stands for hydrogen, C₁-C₃ alkyl,NH₂, amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl or (CH₂)_(n)—Ar group,wherein (CH₂)_(n) and Ar have the meanings given in claim
 1. 3. Acompound according to claim 2, characterized in that A stands for NHgroup and B simultaneously stands for C═O group, R¹ stands forL-cladinosyl group of formula (II) and R², R³ and R⁴ are mutually thesame and stand for hydrogen, R⁵ and R⁶ together with intervening atomsform an additional ring of formula (IVb), wherein Z stands for C═Ogroup.
 4. A compound according to claim 1, characterized in that Astands for C═O group and B simultaneously stands for NH group, R¹ standsfor L-cladinosyl group of formula (II) and R², R³ and R⁴ are mutuallythe same and stand for hydrogen, R⁵ and R⁶ together with interveningatoms form an additional ring of formula (IV), wherein Z stands for CH₂,C═O, C(NH), SO, SO₂, CH₂CO, COCH₂, CH₂CH₂CO, COCH₂CH₂ or CH₂CH₂, and Xstands for hydrogen, C₁-C₃ alkyl, NH₂, amino-C₁-C₃ alkyl or amino-C₁-C₃dialkyl or (CH₂)_(n)—Ar group, wherein (CH₂)_(n) and Ar have themeanings given in claim
 1. 5. A compound according to claim 4,characterized in that A stands for C═O group and B simultaneously standsfor NH group, R¹ stands for L-cladinosyl group of formula (II) and R²,R³ and R⁴ are mutually the same and stand for hydrogen, R⁵ and R⁶together with intervening atoms form an additional ring of formula(IVb), wherein Z stands for C═O group.
 6. A compound according to claim1, characterized in that A stands for NH group and B simultaneouslystands for C═O group, R¹ stands for OH and R², R³ and R⁴ are mutuallythe same and stand for hydrogen, R⁵ and R⁶ together with interveningatoms form an additional ring of formula (IV), wherein Z stands for CH₂,C═O, C(NH), SO, SO₂, CH₂CO, COCH₂, CH₂CH₂CO, COCH₂CH₂ or CH₂CH₂, and Xstands for hydrogen, C₁-C₃ alkyl, NH₂, amino-C₁-C₃ alkyl oramino-C₁-C₃-dialkyl or (CH₂)_(n)—Ar group, wherein (CH₂)_(n) and Ar havethe meanings given in claim
 1. 7. A compound according to claim 6,characterized in that A stands for NH group and B simultaneously standsfor C═O group, R¹ stands for OH and R², R³ and R⁴ are mutually the sameand stand for hydrogen, R⁵ and R⁶ together with intervening atoms forman additional ring of formula (IVb), wherein Z stands for C═O group. 8.A compound according to claim 1, characterized in that A stands for NHgroup and B simultaneously stands for C═O group, R¹ stands for OH, andR² and R⁴ are mutually the same and stand for hydrogen, R³ stands forC₁-C₄ alkanoyl group, R⁵ and R⁶ together with intervening atoms form anadditional ring of formula (IVb), wherein Z stands for C═O group.
 9. Acompound according to claim 8, characterized in that A stands for NHgroup and B simultaneously stands for C═O group, R¹ stands for OH, andR² and R⁴ are mutually the same and stand for hydrogen, R³ stands foracetyl group, R⁵ and R⁶ together with intervening atoms form anadditional ring of formula (IVb), wherein Z stands for C═O group.
 10. Acompound according to claim 1, characterized in that A stands for C═Ogroup and B simultaneously stands for NH group, R¹ stands for OH and R²,R³ and R⁴ are mutually the same and stand for hydrogen, R⁵ and R⁶together with intervening atoms form an additional ring of formula (IV),wherein Z stands for CH₂, C═O, C(NH), SO, SO₂, CH₂CO, COCH₂, CH₂CH₂CO,COCH₂CH, or CH₂CH₂, and X stands for hydrogen, C₁-C₃ alkyl, NH₂,amino-C₁-C₃ alkyl or amino-C₁-C₃-dialkyl or (CH₂)_(n)—Ar group, wherein(CH₂)_(n) and Ar have the meanings given in claim
 1. 11. A compoundaccording to claim 10, characterized in that A stands for C═O group andB simultaneously stands for NH group, R¹ stands for OH and R², R³ and R⁴are mutually the same and stand for hydrogen, R⁵ and R⁶ together withintervening atoms form an additional ring of formula (IV), wherein Zstands for C═O group.
 12. A compound according to claim 1, characterizedin that A stands for C═O group and B simultaneously stands for NH group,R¹ stands for OH, R² and R⁴ are mutually the same and stand forhydrogen, R³ stands for C₁-C₄ alkanoyl group, R⁵ and R⁶ together withintervening atoms form an additional ring of formula (IVb), wherein Zstands for C═O group.
 13. A compound according to claim 12,characterized in that A stands for C═O group and B simultaneously standsfor NH group, R¹ stands for OH, R² and R⁴ are mutually the same andstand for hydrogen, R³ stands for acetyl group, R⁵ and R⁶ together withintervening atoms form an additional ring of formula (IVb), wherein Zstands for C═O group.
 14. A compound according to claim 1, characterizedin that A stands for NH group and B simultaneously stands for C═O group,R¹ stands for a group of formula (III), wherein Y stands for hydrogen,C₁-C₆ alkyl, C₁-C₆ alkyl group with at least one incorporated O, N or Satom, or Y stands for (CH₂)_(n)—Ar, wherein (CH₂), stands for alkyl andn is 1-10, without or with incorporated O, N or S atoms, and Ar standsfor a 5-10-membered monocyclic or bicyclic aromatic ring comprising 0-3O, N or S atoms which is unsubstituted or substituted with 1-3 groupsrepresenting halogen, OH, OMe, NO₂, NH₂, amino-C₁-C₃ alkyl oramino-C₁-C₃ dialkyl, CN, SO₂NH₂, C₁-C₃ alkyl, R², R³ and R⁴ are mutuallythe same and stand for hydrogen, R⁵ and R⁶ together with interveningatoms form an additional ring of formula (IV), wherein Z stands for CH₂,C═O, C(NH), SO, SO₂, CH₂CO, COCH₂, CH₂CH₂CO, COCH₂CH₂ or CH₂CH₂, and Xstands for hydrogen, C₁-C₃ alkyl, NH₂, amino-C₁-C₃ alkyl or amino-C₁-C₃dialkyl or (CH₂)_(n)—Ar group, wherein (CH₂)_(n) and Ar have the abovemeanings.
 15. A compound according to claim 14, characterized in that Astands for NH group and B simultaneously stands for C═O group, R¹ standsfor a group of formula (III) wherein Y stands for (CH₂)_(n)—Ar, wherein(CH₂)_(n) stands for alkyl and n is 1 and Ar stands for 6-memberedmonocyclic aromatic ring substituted with p-NO₂ group, R², R³ and R⁴ aremutually the same and stand for hydrogen, R⁵ and R⁶ together withintervening atoms form an additional ring of formula (IVb), wherein Zstands for C═O.
 16. A compound according to claim 14, characterized inthat A stands for NH group and B simultaneously stands for C═O group, R¹stands for a group of formula (III) wherein Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n is 1 and Ar stands for6-membered monocyclic aromatic ring substituted with p-OCH₃ group, R²,R³ and R⁴ are mutually the same and stand for hydrogen, R⁵ and R⁶together with intervening atoms form an additional ring of formula(IVb), wherein Z stands for C═O.
 17. A compound according to claim 14,characterized in that A stands for NH group and B simultaneously standsfor C═O group, R¹ stands for a group of formula (III) wherein Y standsfor (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyl and n is 1 and Arstands for a 6-membered monocyclic aromatic ring substituted with p-NH₂group, R², R³ and R⁴ are mutually the same and stand for hydrogen, R⁵and R⁶ together with intervening atoms form an additional ring offormula (IVb), wherein Z stands for C═O.
 18. A compound according toclaim 14, characterized in that A stands for NH group and Bsimultaneously stands for C═O group, R¹ stands for a group of formula(III) wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands foralkyl and n is 1 and Ar stands for 6-membered monocyclic aromatic ringsubstituted with p-OH group, R², R³ and R⁴ are mutually the same andstand for hydrogen, R⁵ and R⁶ together with intervening atoms form anadditional ring of formula (IVb), wherein Z stands for C═O.
 19. Acompound according to claim 14, characterized in that A stands for NHgroup and B simultaneously stands for C═O group, R¹ stands for a groupof formula (III) wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n)stands for alkyl and n is 1 and Ar stands for 6-membered monocyclicaromatic ring substituted with p-Cl, R², R³ and R⁴ are mutually the sameand stand for hydrogen, R⁵ and R⁶ together with intervening atoms forman additional ring of formula (IVb), wherein Z stands for C═O.
 20. Acompound according to claim 14, characterized in that A stands for NHgroup and B simultaneously stands for C═O group, R¹ stands for a groupof formula (III) wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n)stands for alkyl and n is 1 and Ar stands for 6-membered monocyclicaromatic ring substituted with p-SO₂NH₂, R², R³ and R⁴ are mutually thesame and stand for hydrogen, R⁵ and R⁶ together with intervening atomsform an additional ring of formula (IVb), wherein Z stands for C═O. 21.A compound according to claim 14, characterized in that A stands for NHgroup and B simultaneously stands for C═O group, R¹ stands for a groupof formula (III) wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n)stands for alkyl and n is 1 and Ar stands for 6-membered monocyclicaromatic ring substituted with p-NH—(CH₃) group, R², R³ and R⁴ aremutually the same and stand for hydrogen, R⁵ and R⁶ together withintervening atoms form an additional ring of formula (IVb), wherein Zstands for C═O.
 22. A compound according to claim 14, characterized inthat A stands for NH group and B simultaneously stands for C═O group, R¹stands for a group of formula (III) wherein Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n is 1 and Ar stands for6-membered monocyclic aromatic ring substituted with p-N(CH₃)₂ group,R², R³ and R⁴ are mutually the same and stand for hydrogen, R⁵ and R⁶together with intervening atoms form an additional ring of formula(IVb), wherein Z stands for C═O.
 23. A compound according to claim 14,characterized in that A stands for NH group and B simultaneously standsfor C═O group, R¹ stands for a group of formula (III) wherein Y standsfor (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyl and n is 1 and Arstands for 6-membered monocyclic aromatic ring substituted with p-CH₃group, R², R³ and R⁴ are mutually the same and stand for hydrogen, R⁵and R⁶ together with intervening atoms form an additional ring offormula (IVb), wherein Z stands for C═O.
 24. A compound according toclaim 1, characterized in that A stands for C═O group and Bsimultaneously stands for NH group, R¹ stands for a group of formula(III), Y stands for hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl group with atleast one incorporated O, N or S atom, or Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n is 1-10, without or withincorporated O, N or S atoms, and Ar stands for 5-10-membered monocyclicor bicyclic aromatic ring comprising 0-3 O, N or S atoms which isunsubstituted or substituted with 1-3 groups representing halogen, OH,OMe, NO₂, NH₂, amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl, CN, SO₂NH₂,C₁-C₃ alkyl, R², R³ and R⁴ are mutually the same and stand for hydrogen,R⁵ and R⁶ together with intervening atoms form an additional ring offormula (IV), wherein Z stands for CH₂, C═O, C(NH), SO, SO₂, CH₂CO,COCH₂, CH₂CH₂CO, COCH₂CH, or CH₂CH₂, and X stands for hydrogen, C₁-C₃alkyl, NH₂ amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl or (CH₂)_(n)—Argroup, wherein (CH₂)_(n) and Ar have the above meanings.
 25. A compoundaccording to claim 24, characterized in that A stands for C═O group andB simultaneously stands for NH group, R¹ stands for a group of formula(III) wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands foralkyl and n is 1 and Ar stands for 6-membered monocyclic aromatic ringsubstituted with p-NO₂ group, R², R³ and R⁴ are mutually the same andstand for hydrogen, R⁵ and R⁶ together with intervening atoms form anadditional ring of formula (IVb), wherein Z stands for C═O.
 26. Acompound according to claim 24, characterized in that A stands for C═Ogroup and B simultaneously stands for NH group, R¹ stands for a group offormula (III) wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n)stands for alkyl and n is 1 and Ar stands for 6-membered monocyclicaromatic ring substituted with p-OCH₃ group, R², R³ and R⁴ are mutuallythe same and stand for hydrogen, R⁵ and R⁶ together with interveningatoms form an additional ring of formula (IVb), wherein Z stands forC═O.
 27. A compound according to claim 24, characterized in that Astands for C═O group and B simultaneously stands for NH group, R¹ standsfor a group of formula (III) wherein Y stands for (CH₂)_(n)—Ar, wherein(CH₂)N stands for alkyl and n is 1 and Ar stands for 6-memberedmonocyclic aromatic ring substituted with p-NH₂ group, R², R³ and R⁴ aremutually the same and stand for hydrogen, R⁵ and R⁶ together withintervening atoms form an additional ring of formula (IVb), wherein Zstands for C═O.
 28. A compound according to claim 24, characterized inthat A stands for C═O group and B simultaneously stands for NH group, R¹stands for a group of formula (III) wherein Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n is 1 and Ar stands for6-membered monocyclic aromatic ring substituted with p-OH group, R², R³and R⁴ are mutually the same and stand for hydrogen, R⁵ and R⁶ togetherwith intervening atoms form an additional ring of formula (IVb), whereinZ stands for C═O.
 29. A compound according to claim 24, characterized inthat A stands for C═O group and B simultaneously stands for NH group, R¹stands for a group of formula (III) wherein Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n is 1 and Ar stands for6-membered monocyclic aromatic ring substituted with p-Cl, R², R³ and R⁴are mutually the same and stand for hydrogen, R⁵ and R⁶ together withintervening atoms form an additional ring of formula (IVb), wherein Zstands for C═O.
 30. A compound according to claim 24, characterized inthat A stands for C═O group and B simultaneously stands for NH group, R¹stands for a group of formula (III) wherein Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n is 1 and Ar stands for6-membered monocyclic aromatic ring substituted with p-SO₂NH₂, R², R³and R⁴ are mutually the same and stand for hydrogen, R⁵ and R⁶ togetherwith intervening atoms form an additional ring of formula (IVb), whereinZ stands for C═O.
 31. A compound according to claim 24, characterized inthat A stands for C═O group and B simultaneously stands for NH group, R¹stands for a group of formula (III) wherein Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n is 1 and Ar stands for6-membered monocyclic aromatic ring substituted with p-NH—(CH₃) group,R², R³ and R⁴ are mutually the same and stand for hydrogen, R⁵ and R⁶together with intervening atoms form an additional ring of formula(IVb), wherein Z stands for C═O.
 32. A compound according to claim 24,characterized in that A stands for C═O group and B simultaneously standsfor NH group, R¹ stands for a group of formula (III) wherein Y standsfor (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyl and n is 1 and Arstands for 6-membered monocyclic aromatic ring substituted withp-N(CH₃)₂ group, R², R³ and R⁴ are mutually the same and stand forhydrogen, R⁵ and R⁶ together with intervening atoms form an additionalring of formula (IVb), wherein Z stands for C═O.
 33. A compoundaccording to claim 24, characterized in that A stands for C═O group andB simultaneously stands for NH group, R¹ stands for a group of formula(III) wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands foralkyl and n is 1 and Ar stands for 6-membered monocyclic aromatic ringsubstituted with p-CH₃ group, R², R³ and R⁴ are mutually the same andstand for hydrogen, R⁵ and R⁶ together with intervening atoms form anadditional ring of formula (IVb), wherein Z stands for C═O.
 34. Acompound according to claim 1, characterized in that A stands for NHgroup and B simultaneously stands for C═O group, R¹ has the meaning ofthe group of the formula (III), wherein Y stands for hydrogen, C₁-C₆alkyl, C₁-C₆ alkyl group with at least one incorporated O, N or S atom,or Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyl and nstands for 1-10, without or with incorporated O, N or S atoms, and Arstands for 5-10-membered monocyclic or bicyclic aromatic ring containing0-3 O, N or S atoms, which is unsubstituted or substituted with 1-3groups representing halogen, OH, OMe, NO₂, NH₂, amino-C₁-C₃ alkyl oramino-C₁-C₃ dialkyl, CN, SO, NH₂, C₁-C₃ alkyl, R², R³, R⁴, and R⁶ aremutually the same and stand for hydrogen and R⁵ is OH group.
 35. Acompound according to claim 34, characterized in that A stands for NHgroup and B simultaneously stands for C═O group, R¹ has the meaning ofthe group of the formula (III), wherein Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n stands for 1 and Ar stands for6-membered monocyclic aromatic ring substituted with p-NO₂ group, R²,R³, R⁴, and R⁶ are mutually the same and stand for hydrogen and R⁵ isOH.
 36. A compound according to claim 34, characterized in that A standsfor NH group and B simultaneously stands for C═O group, R¹ has themeaning of the group of the formula (III), wherein Y stands for(CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyl and n stands for 1 andAr stands for 6-membered monocyclic aromatic ring substituted withp-OCH₃ group, R², R³, R⁴, and R⁶ are mutually the same and stand forhydrogen and R⁵ is OH.
 37. A compound according to claim 34,characterized in that A stands for NH group and B simultaneously standsfor C═O group, R¹ has the meaning of the group of the formula (III),wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyland n stands for 1 and Ar stands for 6-membered monocyclic aromatic ringsubstituted with p-NH₂ group, R², R³, R⁴, and R⁶ are mutually the sameand stand for hydrogen and R⁵ is OH.
 38. A compound according to claim34, characterized in that A stands for NH group and B simultaneouslystands for C═O group, R¹ has the meaning of the group of the formula(III), wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands foralkyl and n stands for 1 and Ar stands for 6-membered monocyclicaromatic ring substituted with p-OH group, R², R³, R⁴, and R⁶ aremutually the same and stand for hydrogen and R⁵ is OH.
 39. A compoundaccording to claim 34, characterized in that A stands for NH group and Bsimultaneously stands for C═O group, R¹ has the meaning of the group ofthe formula (III), wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n)stands for alkyl and n stands for 1 and Ar stands for 6-memberedmonocyclic aromatic ring substituted with p-Cl, R², R³, R⁴, and R⁶ aremutually the same and stand for hydrogen and R⁵ is OH.
 40. A compoundaccording to claim 34, characterized in that A stands for NH group and Bsimultaneously stands for C═O group, R¹ has the meaning of the group ofthe formula (III), wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n)stands for alkyl and n stands for 1 and Ar stands for 6-memberedmonocyclic aromatic ring substituted with p-SO₂NH₂, R², R³, R⁴, and R⁶are mutually the same and stand for hydrogen and R⁵ is OH.
 41. Acompound according to claim 34, characterized in that A stands for NHgroup and B simultaneously stands for C═O group, R¹ has the meaning ofthe group of the formula (III), wherein Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n stands for 1 and Ar stands for6-membered monocyclic aromatic ring substituted with p-NH—CH₃ group, R²,R³, R⁴, and R⁶ are mutually the same and stand for hydrogen and R⁵ isOH.
 42. A compound according to claim 34, characterized in that A standsfor NH group and B simultaneously stands for C═O group, R¹ has themeaning of the group of the formula (III), wherein Y stands for(CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyl and n stands for 1 andAr stands for 6-membered monocyclic aromatic ring substituted withp-N(CH₃)₂ group, R², R³, R⁴, and R⁶ are mutually the same and stand forhydrogen and R⁵ is OH.
 43. A compound according to claim 34,characterized in that A stands for NH group and B simultaneously standsfor C═O group, R¹ has the meaning of the group of the formula (III),wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyland n stands for 1 and Ar stands for 6-membered monocyclic aromatic ringsubstituted with p-CH₃ group, R², R³, R⁴, and R⁶ are mutually the sameand stand for hydrogen and R⁵ is OH.
 44. A compound according to claim1, characterized in that A stands for C═O group and B simultaneouslystands for NH group, R¹ has the meaning of the group of the formula(III), wherein Y stands for hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl groupwith at least one incorporated O, N or S atom, or Y stands for(CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyl and n stands for 1-10,without or with incorporated O, N or S atoms, and Ar stands for5-10-membered monocyclic or bicyclic aromatic ring containing 0-3 O, Nor S atoms, which is unsubstituted or substituted with 1-3 groupsrepresenting halogen, OH, OMe, NO₂, NH₂, amino-C₁-C₃ alkyl oramino-C₁-C₃ dialkyl, CN, SO₂NH₂, C₁-C₃ alkyl, R², R⁴, and R⁶ aremutually the same and stand for hydrogen and R⁵ is OH group.
 45. Acompound according to claim 44, characterized in that A stands for C═Ogroup and B simultaneously stands for NH group, R¹ has the meaning ofthe group of the formula (III), wherein Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n stands for 1 and Ar stands for6-membered monocyclic aromatic ring substituted with p-NO₂ group, R²,R³, R⁴, and R⁶ are mutually the same and stand for hydrogen and R⁵ isOH.
 46. A compound according to claim 44, characterized in that A standsfor C═O group and B simultaneously stands for NH group, R¹ has themeaning of the group of the formula (III), wherein Y stands for(CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyl and n stands for 1 andAr stands for 6-membered monocyclic aromatic ring substituted withp-OCH₃ group, R², R³, R⁴, and R⁶ are mutually the same and stand forhydrogen and R⁵ is OH.
 47. A compound according to claim 44,characterized in that A stands for C═O group and B simultaneously standsfor NH group, R¹ has the meaning of the group of the formula (III),wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyland n stands for 1 and Ar stands for 6-membered monocyclic aromatic ringsubstituted with p-NH₂ group, R², R³, R⁴, and R⁶ are mutually the sameand stand for hydrogen and R⁵ is OH.
 48. A compound according to claim44, characterized in that A stands for C═O group and B simultaneouslystands for NH group, R¹ has the meaning of the group of the formula(III), wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands foralkyl and n stands for 1 and Ar stands for 6-membered monocyclicaromatic ring substituted with p-OH group, R², R³, R⁴, and R⁶ aremutually the same and stand for hydrogen and R⁵ is OH.
 49. A compoundaccording to claim 44, characterized in that A stands for C═O group andB simultaneously stands for NH group, R¹ has the meaning of the group ofthe formula (III), wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n)stands for alkyl and n stands for 1 and Ar stands for 6-memberedmonocyclic aromatic ring substituted with p-Cl, R², R³, R⁴, and R⁶ aremutually the same and stand for hydrogen and R⁵ is OH.
 50. A compoundaccording to claim 44, characterized in that A stands for C═O group andB simultaneously stands for NH group, R¹ has the meaning of the group ofthe formula (III), wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n)stands for alkyl and n stands for 1 and Ar stands for 6-memberedmonocyclic aromatic ring substituted with p-SO₂NH₂, R², R³, R⁴, and R⁶are mutually the same and stand for hydrogen and R⁵ is OH.
 51. Acompound according to claim 44, characterized in that A stands for C═Ogroup and B simultaneously stands for NH group, R¹ has the meaning ofthe group of the formula (III), wherein Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n stands for 1 and Ar stands for6-membered monocyclic aromatic ring substituted with p-NH—CH₃ group, R²,R³, R⁴, and R⁶ are mutually the same and stand for hydrogen and R⁵ isOH.
 52. A compound according to claim 44, characterized in that A standsfor C═O group and B simultaneously stands for NH group, R¹ has themeaning of the group of the formula (III), wherein Y stands for(CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyl and n stands for 1 andAr stands for 6-membered monocyclic aromatic ring substituted withp-N(CH₃)₂ group, R², R³, R⁴, and R⁶ are mutually the same and stand forhydrogen and R⁵ is OH.
 53. A compound according to claim 44,characterized in that A stands for C═O group and B simultaneously standsfor NH group, R¹ has the meaning of the group of the formula (III),wherein Y stands for (CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyland n stands for 1 and Ar stands for 6-membered monocyclic aromatic ringsubstituted with p-CH₃ group, R², R³, R⁴, and R⁶ are mutually the sameand stand for hydrogen and R⁵ is OH.
 54. A compound according to claim1, characterized in that A stands for NH group and B simultaneouslystands for C═O group, R¹ and R² together stand for a ketone, R³ and R⁶are mutually the same and stand for hydrogen and R⁴ and R⁵ togetherstand for a ketone.
 55. A compound according to claim 1, characterizedin that A stands for C═O group and B simultaneously stands for NH group,R¹ and R² together stand for a ketone, R³ and R⁶ are mutually the sameand stand for hydrogen and R⁴ and R⁵ together stand for a ketone.
 56. Acompound according to claim 1, characterized in that A stands for NHgroup and B simultaneously stands for C═O group, R¹ and R² togetherstand for a ketone, R³ and R⁴ are mutually the same and stand forhydrogen, R⁵ and R⁶ together with intervening atoms form an additionalring of formula (IV), wherein Z stands for CH₂, C═O, C(NH), SO, SO₂,CH₂CO, COCH₂, CH₂CH₂CO, COCH₂CH₂ or CH₂CH₂, and X stands for hydrogen,C₁-C₃ alkyl, NH₂, amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl or(CH₂)_(n)—Ar group, wherein (CH₂)₂ and Ar have the meanings given inclaim
 1. 57. A compound according to claim 56, characterized in that Astands for NH group and B simultaneously stands for C═O group, R¹ and R²together stand for a ketone, R³ and R⁴ are mutually the same and standfor hydrogen, R⁵ and R⁶ together with intervening atoms form anadditional ring of formula (IVb), wherein Z stands for C═O.
 58. Acompound according to claim 1, characterized in that A stands for C═Ogroup and B simultaneously stands for NH group, R¹ and R² together standfor a ketone, R³ and R⁴ are mutually the same and stand for hydrogen, R⁵and R⁶ together with intervening atoms form an additional ring offormula (IV), wherein Z stands for CH₂, C═O, C(NH), SO, SO₂, CH₂CO,COCH₂, CH₂CH₂CO, COCH₂CH₂ or CH₂CH₂, and X stands for hydrogen, C₁-C₃alkyl, NH₂, amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl or (CH₂)_(n)—Argroup, wherein (CH₂)_(n) and Ar have the meanings given in claim
 1. 59.A compound according to claim 1, characterized in that A stands for C═Ogroup and B simultaneously stands for NH group, R¹ and R² together standfor a ketone, R³ and R⁴ are mutually the same and stand for hydrogen, R⁵and R⁶ together with intervening atoms form an additional ring offormula (IVb), wherein Z stands for C═O.
 60. A process for preparationof a compound of formula (I),

or its pharmaceutically acceptable addition salts, with inorganic ororganic acids, or hydrates thereof, wherein A stands for NH group and Bsimultaneously stands for C═O group, or A stands for C═O group and Bsimultaneously stands for NH group, R¹ stands for OH group, L-cladinosylgroup of formula (II),

or R¹ stands for a group of formula (III),

 wherein Y stands for hydrogen, C₁-C₆ alkyl, C₁-C₆ alkyl group with atleast one incorporated O, N or S atom or Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n), stands for alkyl and n stands for 1-10, with orwithout incorporated O, N or S atoms, and Ar stands for 5-10-memberedmonocyclic or bicyclic aromatic ring containing 0-3 O, N or S atoms,which is unsubstituted or substituted with 1-3 groups representinghalogen, OH, OMe, NO₂, NH₂, amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl,CN, SO₂NH₂, C₁-C₃ alkyl, or R¹ together with R² stands for oxo, R²stands for hydrogen or together with R¹ stands for oxo, R³ stands forhydrogen or C₁-C₄ alkanoyl group, R⁴ stands for hydrogen or togetherwith R⁵ stands for oxo, R⁵ stands for OH, NH₂, amino-C₁-C₃ alkyl oramino-C₁-C₃ dialkyl, O(CH₂)_(n)Ar or S(CH₂)_(n)Ar, wherein (CH₂)_(n) andAr have the above meanings, or together with R⁴ stands for oxo, withproviso that when R⁵ stands for OH, R¹ does not stand for L-cladinosylgroup of formula (II) or OH, R⁶ stands for hydrogen, C₁-C₆ alkyl, heteroC₁-C₆ alkyl group wherein said hetero atom is O, N or S, or (CH₂)_(n)—Argroup, wherein (CH₂)_(n) and Ar have the above meanings, with provisothat when R⁶ stands for H, R¹ does not stand for L-cladinosyl group offormula (II) or OH, or R⁵ and R⁶ together with intervening atoms form anadditional ring of formula (IV)

 wherein Z stands for CH₂, C═O, C(NH), SO, SO₂, CH₂CO, COCH₂, CH₂CH₂CO,COCH₂CH₂ or CH₂CH₂, and X stands for hydrogen, C₁-C₃ alkyl, NH₂,amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl or (CH₂)_(n)—Ar group, wherein(CH₂)_(n) and Ar have the above meanings, characterized in that, A/ a)6-O-methyl-9a-aza-9a-homoerythromycin A or6-O-methyl-8a-aza-8a-homoerythromycin A of the general formula (I),wherein A stands for NH group and B simultaneously stands for C═O group,or A stands for C═O group and B simultaneously stands for NH group, R¹stands for L-cladinosyl group of the formula (II) and R², R³, R⁴ and R⁶are mutually the same and stand for hydrogen and R⁵ stands for OH group,obtained according to PCT/HR 99/00004, 4/99, are subjected to a reactionwith ethylene carbonate in the presence of inorganic or organic bases,preferably potassium carbonate, in a reaction-inert solvent, preferablyin ethyl acetate, yielding corresponding 11,12-cyclic carbonates of thegeneral formula (I), wherein A stands for NH group and B simultaneouslystands for C═O group, or A stands for C═O group and B simultaneouslystands for NH group, R¹ stands for L-cladinosyl group of the formula(II) and R², R³ and R⁴ are mutually the same and stand for hydrogen, R⁵and R⁶ together with intervening atoms form an additional ring of theformula (IVb), wherein Z stands for C═O group, which are subsequentlysubjected to b) hydrolysis with strong acids, preferably with 0.25-1.5 Nhydrochloric acid, in a mixture of water and lower alcohols, preferablymethanol, ethanol or isopropanol, over 10-30 hours at room temperature,yielding 3-decladinosyl derivatives of the general formula (I), whereinA stands for NH group and B simultaneously stands for C═O group, or Astands for C═O group and B simultaneously stands for NH group, R¹ standsfor OH group, R², R³ and R⁴ are mutually the same and stand forhydrogen, and R⁵ and R⁶ together with intervening atoms form anadditional ring of the formula (IVb), wherein Z stands for C═O group,which are subsequently subjected to c) a selective acylation of ahydroxyl group in 2′-position with chlorides or anhydrides of carboxylicacids with up to 4 carbon atoms, preferably with acetic acid anhydride,in the presence of inorganic or organic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, triethyl amine,pyridine, tributylamine, preferably sodium hydrogen carbonate, in areaction-inert solvent such as methylene chloride, dichloroethane,acetone, pyridine, ethyl acetate, tetrahydrofuran, preferably methylenechloride, at a temperature from 0-30° C., yielding 2′-O-acyl derivativesof the general formula (I), wherein A stands for NH group and Bsimultaneously stands for C═O group, or A stands for C═O group and Bsimultaneously stands for NH group, R¹ stands for OH group, R² and R⁴are mutually the same and stand for hydrogen, R³ stands for acetyl andR⁵ and R⁶ together with intervening atoms form an additional ring offormula (IVb), wherein Z stands for C═O group, which are optionallysubjected to d1) a reaction with mixed anhydrides of carboxylic acids offormula Y—COO—R′, wherein Y stands for hydrogen, C₁-C₆ alkyl, heteroC₁-C₆ alkyl group wherein said hetero atom is O, N or S, or Y stands for(CH₂)_(n)—Ar, wherein (CH₂)_(n) stands for alkyl and n is 1-10, withoutor with incorporated O, N or S atoms, and Ar stands for 5-10-memberedmonocyclic or bicyclic aromatic ring comprising 0-3 O, N or S atomswhich is unsubstituted or substituted with 1-3 groups representinghalogen, OH, OMe, NO₂, NH₂, amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl,CN, SO₂NH₂, C₁-C₃ alkyl and R¹ represents a group which is usually usedfor the preparation of mixed anhydrides such as pivaloyl,p-toluenesulfonyl, isobutoxycarbonyl, ethoxycarbonyl orisopropoxycarbonyl groups, in the presence of inorganic or organicbases, in a reaction-inert solvent, preferably in methylene chloride, ata temperature from 0-30° C. over 3-100 hours, yielding 3-acylderivatives of the general formula (I), wherein R¹ stands for a group offormula (III), Y has the above meanings, A stands for NH group and Bsimultaneously stands for C═O group, or A stands for C═O group and Bsimultaneously stands for NH group, R² and R⁴ are mutually the same andstand for hydrogen, R³ stands for acetyl and R⁵ and R⁶ together withintervening atoms form an additional ring of formula (IVb), wherein Zstands for C═O group, which are subsequently subjected to deprotectionwith lower alcohols, preferably in methanol, at a temperature from roomtemperature to the reflux temperature of the solvent, yielding acompound of the general formula (I), wherein R3 stands for hydrogen andall remaining substituents have the above meanings, or to d2) oxidationof a hydroxyl group in C-3 position of the aglycone ring according to amodified Moffat-Pfitzner process with N-N-dimethylaminopropyl-3-ethyl-carbodiimide in the presence of dimethyl sulfoxideand pyridinium trifluoroacetate as catalyst, in an inert organicsolvent, preferably in methylene chloride, at a temperature from 10° C.to room temperature, yielding 3-oxo derivatives of the general formula(I), wherein A stands for NH group and B simultaneously stands for C═Ogroup, or A stands for C═O group and B simultaneously stands for NHgroup, R¹ together with R² stands for oxo, R³ stands for acetyl group,R⁴ stands for hydrogen and R⁵ and R⁶ together with intervening atomsform an additional ring of formula (IVb), wherein Z stands for C═Ogroup, which are subsequently subjected to deprotection in loweralcohols, preferably in methanol, at a temperature from room temperatureto the reflux temperature of the solvent, yielding a compound of thegeneral formula (I), wherein R³ stands for hydrogen and all remainingsubstituents have the above meanings, or B/ a)6-O-methyl-9a-aza-9a-homoerythromycin A or6-O-methyl-8a-aza-8a-homoerythromycin A of the general formula (I),wherein A stands for NH group and B simultaneously stands for C═O group,or A stands for C═O group and B simultaneously stands for NH group, R¹stands for L-cladinosyl group of the formula (II) and R², R³, R⁴ and R⁶are mutually the same and stand for hydrogen and R⁵ stands for OH group,obtained according to PCT/HR 99/00004, 4/99, are subjected to hydrolysiswith strong acids, then to a selective acylation of 2′-position, whichare then optionally subjected to b1) a reaction with mixed anhydridesand deprotection as given above, yielding a compound of the generalformula (I), wherein R¹ has the meaning of a group of the formula (III),wherein Y stands for hydrogen, C₁-C₆ alkyl, hetero C₁-C₆ alkyl groupwherein said hetero atom is O, N or S, or Y stands for (CH₂)_(n)—Ar,wherein (CH₂)_(n) stands for alkyl and n is 1-10, without or withincorporated O, N or S atoms, and Ar stands for a 5-10-memberedmonocyclic or bicyclic aromatic ring containing 0-3 O, N or S atoms,which is unsubstituted or substituted with 1-3 groups representinghalogen, OH, OMe, NO₂, NH₂, amino-C₁-C₃ alkyl or amino-C₁-C₃ dialkyl,CN, SO₂NH₂, C₁-C₃ alkyl, R², R³, R⁴, and R⁶ are mutually the same andstand for hydrogen and R⁵ is OH group, or to b2) oxidation of hydroxylgroups in C-3 and C-11 positions of an aglycone ring according to amodified Moffat-Pfitzner process as given above, and deprotection,yielding a compound of the general formula (I), wherein A stands for NHgroup and B simultaneously stands for C═O group, or A stands for C═Ogroup and B simultaneously stands for NH group, R¹ together with R²stands for an oxo, R³ and R⁶ are mutually the same and stand forhydrogen and R⁴ together with R⁵ stands for an oxo, or  alternatively,compounds obtained according to the process Ad1) can be prepared bysubjecting the compounds from the step Bb1) to a reaction with ethylenecarbonate in a manner as described in Aa), or  alternatively, compoundsfrom the step Ab) can be obtained by changing the sequence of thereaction steps in such a manner that6-O-methyl-9a-aza-9a-homoerythromycin A or6-O-methyl-8a-aza-8a-homoerythromycin A obtained according to PCT/HR99/00004, 4/99, are first subjected to hydrolysis with strong acids asdescribed in Ab) and then to a reaction with ethylene carbonate in amanner described in Aa), or  alternatively, the compounds from Ad2) canbe obtained in such a manner that3-decladinosyl-3-oxo-6-O-methyl-9a-aza-9a-homoerythromycin A or3-decladinosyl-3-oxo-6-O-methyl-8a-aza-8a-homo-erythromycin A, obtainedaccording to PCT/HR 99/00004, 4/99, are subjected to a reaction withethylene carbonate in a manner described in the step Aa),  and forobtaining their pharmaceutically acceptable addition salts, the novelcompounds from the class of 6-O-methyl-9a-aza-9a-homo- and6-O-methyl-8a-aza-8a-homoerythromycins A of the general formula (I),wherein A, B, R¹, R², R³, R⁴, R⁵ and R⁶ have the above meanings, arereacted with an at least equimolar amount of a suitable inorganic ororganic acid such as hydrochloric, hydroiodic, sulfuric, phosphoric,acetic, propionic, trifluoroacetic, maleic, citric, stearic, succinic,ethylsuccinic, methanesulfonic, benzenesulfonic, p-toluenesulfonic,laurylsulfonic acid and the like, in a reaction-inert solvent, and byisolating by means of filtration if they are insoluble in thereaction-inert solvent, or precipitation by means of a non-solvent or ofevaporation of the solvent, most frequently by lyophilization. 61.Pharmaceutical composition useful for treatment of bacterial infectionsin humans and animals comprising therapeutically effective amounts of acompound of formula (I) or its pharmaceutically acceptable additionsalts according to claim 1, in combination with a pharmaceuticallyacceptable carrier.
 62. Method for treating bacterial infections inhumans and animals comprising administering to humans and animalsrequired therapeutically effective amounts of a compound of the formula(I) or pharmaceutically acceptable addition salts thereof according toclaim 1, in combination with a pharmaceutically acceptable carrier.